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LOSING FAITH IN MEDICAL RESEARCH – A LONG AND WINDING ROAD

DR MALCOLM KENDRICK

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You are about to enter

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CLEAR YOUR MIND

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BLUE PILL, RED PILL

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WESTERN MEDICINE IS MIRACULOUS

AMPUTATION, OLD STYLE

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WESTERN MEDICINE IS MIRACULOUS

During the early 19th century hospitals were known as the 'gateway to death' and medical students crowded into large halls to watch as patients suffered.

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ROBERT LISTON – FASTEST KNIFE IN THE WEST END

Before anaesthetic became available amputations happened while patients were awake and able to feel the excruciating pain of the surgery.

So doctors who removed limbs the quickest gained in popularity, with Robert Liston, a surgeon and Scotsman, gaining the record for amputating a leg in just 30 seconds.

Dr Liston, 'The fastest knife in the West End,' ran a surgery in Bond Street, Mayfair, London, from 1840 to 1846 - the year anaesthetic was first used.

On one occasion Dr Liston was so quick to amputate a leg he chopped off his patient's testicle as well.

And during another surgery he gained a 300 per cent mortality rate after accidentally cutting off three of his assistant's fingers and frightening a spectator to death.

The spectator died when Dr Liston wielded his knife back and swiped at his coat, causing him to fall down dead from the shock.

Both the assistant and the patient later died of gangrene after their wounds became infected

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WESTERN MEDICINE IS MIRACULOUS

Anaesthetics

Sterile operating techniques

Antibiotics

Thank God

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NOTHING IS PERFECT

There is no perfect system
Personal bias and beliefs
Miasma, removal of toxic colon, the radical mastectomy, tonsillectomies, strict bed rest following a heart attack….

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MIASMA

Plague transmitted by unpleasant smells
The mask had holes into which was placed theriac and/or nutmeg

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THERIAC

Preventive medicine for two thousand years
A small dose of a poison to build up immunity
Hahnemann and Jenner

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HOW I USED TO BE

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HOW I AM NOW

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MY OWN RED PILL

"Can you do addition?" the White Queen asked. "What's one and one and one and one and one and one and one and one and one and one?" "I don't know," said Alice. "I lost count.”
‘Difficulty is a coin the learned make use of like jugglers, to conceal the inanity of their art.’ Michel de Montaigne

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THE STARTING POINT – GLENEAGLES HOTEL

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RED PILL – MRC TRIAL (17,354 PARTICIPANTS OVER 5 YEARS)

The primary results
The stroke rate was reduced: 60 strokes occurred in the treated group and 109 in the placebo group
No difference in coronary events: 222 events occurred on active treatment and 234 in the placebo group
For mortality from all causes treatment made no difference to the rates
248 deaths in the treated group and 253 in the placebo group

https://pubmed.ncbi.nlm.nih.gov/2861880/

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RED PILL – MRC TRIAL (17,354 PATIENTS OVER 5 YEARS)

Five less deaths after forty- three thousand years of treatment
Eight thousand six hundred years to ‘prevent’ one death
Çatalhöyük – nine-thousand-year-old city in Turkey
One of these people would still be alive….

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RED PILL

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EVERYONE ELSE

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ME

Say what!
Is that a red pill in your hand

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LONG AND WINDING ROAD

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CENTERS FOR DISEASE CONTROL AND PREVENTION (CDC)

The United States’ long-standing vaccine safety program closely and constantly monitors the safety of vaccines.
A critical part of the program, CDC’s Immunization Safety Office identifies possible vaccine side effects and conducts studies to determine whether health problems are caused by vaccines.
Data show that the current U.S. vaccine supply is the safest in history.

https://www.cdc.gov/vaccinesafety/index.html

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LOST FAITH

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SAY WHAT?

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WHERE THE RED PILL GETS YOU

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THE LONG AND WINDING ROAD

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THE DIET-HEART HYPOTHESIS

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EAT YOUR HEART OUT

James Le Fanu
Now a friend
First book questioning the diet heart hypothesis

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Deaths from heart disease

Energy from fat in the diet

http://www.heartstats.org

/uploads/documents

%5CPDF.pdf

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COUNTRY	SATURATED FAT INTAKE	CHD DEATHS Per 100/000/yr (men < 65)	CHOLESTEROL LEVELS
Georgia	5.2%	235	5.0mmol/l
Azerbaijan	5.7%	219	5.0mmol/l
Ukraine	7.6%	208	5.1mmol/l
Russia	8.3%	267	5.1mmol/l
Israel	8.6%	44	5.6mmol/l
Spain	10.9%	33	5.6mmol/l
Italy	11.8%	36	5.9mmol/l
UK	13.5%	76	6.0mmol/l
Switzerland	15.3%	32	6.4mmol/l
France	15.5%	24	5.9mmol/l

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CHOLESTEROL AND DEATH

‘Comparison of the prediction by

27 different factors of

coronary heart disease and death

in men and women of the

Scottish heart health study:

cohort study.’

BMJ 1997;315:722

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CHOLESTEROL LEVELS AND RISK OF DEATH

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CHOLESTEROL AND CARDIOVASCULAR DEATHS

https://www.bmj.com/content/368/bmj.m131

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TWO PLUS TWO EQUALS FIVE

‘In the end, the Party would announce that two and two made five, and you would have to believe it.’ [1984 – George Orwell].
Natural herd immunity should not be used as a means of pandemic control…. We need to focus on using successful virus suppression strategies until we reach herd immunity with the new vaccines*

*https://blogs.bmj.com/bmj/2020/12/17/natural-herd-immunity-should-not-be-used-as-a-means-of-pandemic-control/

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TWO PLUS TWO EQUALS FIVE = MONEY

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MONEY

Dr Robert Califf (Obama’s nominee for the head of the FDA)
Senator Lamar Alexander of Tennessee, the Republican who chairs the committee, said Califf had been through an exhaustive vetting process to make sure he had no conflicts of interest.
“My staff tells me they haven’t found anything that would call into doubt your ability to lead the FDA fairly and impartially,” he said.

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MONEY

Conflict of Interest statement Dr Califf (took me five seconds on the mighty google)
Dr Califf currently holds the post of Deputy Commissioner for Medical Products and Tobacco, US Food and Drug Administration. Prior to holding this post, Dr Califf received grant funding from the Patient-Centered Outcomes Research Institute, the National Institutes of Health, the US Food and Drug Administration, Merck, Roche, Aterovax, Bayer, Janssen Pharmaceuticals, Eli Lilly & Company, and Schering-Plough; grants and personal fees from Novartis, Amylin, Scios, and Bristol-Myers Squibb/Bristol-Myers Squibb Foundation; and personal fees from WebMD, Kowa Research Institute, Nile, Parkview, Orexigen, Pozen, Servier International, Bayer Healthcare, Bayer Pharma AG, CV Sight, Daiichi Sankyo/Lilly, Gambro, Gilead, Heart.org–Bayer, Medscape, Pfizer, Regeneron, TMC, GlaxoSmithKline, Genentech, Heart.org–Daiichi Sankyo, and Amgen. �Dr Califf also reported holding equity in Nitrox/N30 and Portola.

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MONEY

“My staff tells me they haven’t found anything that would call into doubt your ability to lead the FDA fairly and impartially,” he said.

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MONEY – LET’S TRY THAT AGAIN

“My staff tells me they haven’t found anything that would call into doubt your ability to lead the FDA fairly and impartially,” he said. (Said he).

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‘It is simply no longer possible to believe much of the clinical research that is published, or to rely on the judgement of trusted physicians or authoritative medical guidelines. �Marcia Angell

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LOSING FAITH IN MEDICAL RESEARCH

‘The poor quality of medical research is widely acknowledged, yet disturbingly the leaders of the medical profession seem only minimally concerned about the problems and make no apparent efforts to find a solution.’ �Richard Smith

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LOSING FAITH

‘The case against science is straightforward: much of the scientific literature, perhaps half, may simply be untrue…science has taken a turn towards darkness.’ Richard Horton

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WHAT HAPPENS WHEN MONEY TAKES OVER?

“Moreover, for many current scientific fields, claimed research findings may often be simply accurate measures of the prevailing bias.’
“It is more likely for a research claim to be false than true.’
J Ioannides: ‘Why most published research findings are false’.

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CONCRETE EXAMPLE

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PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 9 (PCSK9) -INHIBITORS

Statin $40/year
PCSK9-inhibitor $8,000/year
Two hundred times as expensive (or thereabouts)
UK $80,000,000,000/year
US $800,000,000,000/year (eight hundred billion)

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REPATHA – EVOLUCAMAB

Landmark outcomes study shows that Repatha® (Evolocumab) decreases LDL-C To unprecedented low levels and reduces risk of cardiovascular events with no new safety issues

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REPATHA - PCSK9-INHBITOR

As reported in Medscape
The study, which included more that 27,000 participants with atherosclerotic CVD and already receiving statins showed that patients who received injections of Repatha/evolucamab had…
15% reduced risk for composite of MI, stroke, CV death, coronary revascularisation and unstable angina hospitalisation at 22 months (P<0.001)

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REPATHA

For a key secondary end point – MI, stroke, CV death…
The study showed a 20% risk reduction for the evolucamab group (p<0.001).

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THE RED PILL

"Can you do addition?" the White Queen asked. "What's one and one and one and one and one and one and one and one and one and one?" "I don't know," said Alice. "I lost count.“

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REPATHA (EVOLUCAMAB)

This drug was licensed purely on its effect on reducing LDL (bad cholesterol) by very nearly 60%
It was assumed that this would reduce cardiovascular disease deaths (because we all know that raised LDL causes cardiovascular disease. Heart attacks, strokes and suchlike).
Then, there was the FOURIER study
For a key secondary end point – MI, stroke, CV death…
The study showed a 20% risk reduction for the evolucamab group (p<0.001)
Myocardial Infarction and Stroke – remember this
REMEMBER THIS!

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REPATHA – OVERALL MORTALITY

Total number of deaths in the placebo group = 426
Total number of deaths in the Repatha group = ?

444

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REPATHA – CARDIOVASCULAR MORTALITY

Restoring mortality data in the FOURIER cardiovascular outcomes trial of evolocumab in patients with cardiovascular disease: a reanalysis based on regulatory data

Restoring mortality data in the FOURIER cardiovascular outcomes trial of evolocumab in patients with cardiovascular disease: a reanalysis based on regulatory data | BMJ Open

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REPATHA CARDIOVASCULAR MORALITY

After readjudication, deaths of cardiac origin were numerically higher in the evolocumab group than in the placebo group, suggesting possible cardiac harm.
At the time the trial was terminated early, a non-significantly higher risk of cardiovascular mortality was observed with evolocumab, which was numerically greater in our readjudication.
A complete restoration of the FOURIER trial data is required.
In the meantime, clinicians should be sceptical about prescribing evolocumab for patients with established atherosclerotic cardiovascular disease
Cardiovascular deaths in Repatha arm 113: Deaths in placebo group 88

Restoring mortality data in the FOURIER cardiovascular outcomes trial of evolocumab in patients with cardiovascular disease: a reanalysis based on regulatory data | BMJ Open

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RESTORING INVISIBLE AND ABANDONED TRIALS (RIAT)

The Restoring Invisible and Abandoned Trials (RIAT) initiative is an international effort to tackle bias in research reporting. Its goal is to provide more accurate information to patients and other healthcare decision makers.

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BORING BIT

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FOURIER - REANALYSIS

We were surprised to learn from readjudication of FOURIER that the cause of death was ‘Undetermined’ for 35.4% of all deaths.
Similar unrecognised uncertainties probably apply to the apparent results of many other trials.
We were surprised to find no evidence that autopsy was performed after any death.
Autopsies are the most effective tool to discover unexpected adverse events and causes of death, especially in pivotal trials of new drugs

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FOURIER - REANALYSIS

When reviewing the death narratives in the CSR, we observed 91 deaths classified by the local investigator as ‘Undetermined’,
But subsequently adjudicated by the FOURIER clinical-events committee as ‘Sudden Cardiac’ deaths without any clinical evidence to support this change.
It is misleading to categorise deaths of unknown cause as ‘Sudden Cardiac’, because the latter term implies a relationship to acute myocardial infarction or dysrhythmia of ischaemic origin.
A Cochrane systematic review provides evidence against that assumption and a study of 1000 sudden deaths investigated by autopsy showed that only 41% of sudden deaths are due to myocardial infarction.
Therefore, a critically important error in the NEJM reporting of FOURIER is the adjudication of all ‘sudden’ deaths as sudden cardiac deaths, without supporting evidence.

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PCSK9 INHIBITORS IN GENERAL (AND EZETIMIBE)

‘PCSK9 inhibitors and ezetimibe with or without statin therapy for cardiovascular risk reduction: a systematic review and network meta-analysis.’
Conclusions Ezetimibe or PCSK9 inhibitors may reduce non-fatal MI and stroke in adults at very high or high cardiovascular risk who are receiving maximally tolerated statin therapy or are statin-intolerant, but not in those with moderate and low cardiovascular risk
Adding ezetimibe or PCSK9 inhibitor as add-on therapies or in statin-intolerant adults had no significant effect on all-cause or cardiovascular mortality

PCSK9 inhibitors and ezetimibe with or without statin therapy for cardiovascular risk reduction: a systematic review and network meta-analysis | The BMJ

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SO WHAT DO WE KNOW?

We know that many trials are buried (RIAT) - note to self MCE
We know that investigators make up causes of death
We know that the FDA doesn’t do its job
We know that PSCK9 inhibitors make billions, and will make many more

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PCSK9 INIBITORS

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THE JOY OF PCSK9 INHIBITORS

What You Need to Know About PCSK9 Inhibitors: From Web MD
In fact, one review of studies found that PCSK9 inhibitors slash LDL levels by an average of 47%. This protects your heart: The drugs were shown to reduce the risk of heart attack by 27%.

How Do PCSK9 Inhibitors Lower Cholesterol? (webmd.com)

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HOW I AM NOW

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‘It is simply no longer possible to believe much of the clinical research that is published, or to rely on the judgement of trusted physicians or authoritative medical guidelines. �Marcia Angell

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MEDICAL RESEARCH IS BROKEN